Treatment of chronic tubulointerstitial disease: A new concept Keith A. Hruska  Kidney International  Volume 61, Issue 5, Pages 1911-1922 (May 2002) DOI: 10.1046/j.1523-1755.2002.00331.x Copyright © 2002 International Society of Nephrology Terms and Conditions

Figure 1 Effects of obstruction-induced injury on the collecting duct epithelium. The epithelium undergoes rapid changes involving loss of many features of its terminally differentiated phenotype. The apical microvilli become effaced; cell height is reduced; the tight junctions lose many of their properties and functions; ion transport is reduced and can become non-vectorial. Extracellular matrix production is increased possibly because of transdifferentiation to interstitial myofibroblasts. Kidney International 2002 61, 1911-1922DOI: (10.1046/j.1523-1755.2002.00331.x) Copyright © 2002 International Society of Nephrology Terms and Conditions

Figure 2 Recovery of renal function following release of unilateral ureteral obstruction in three protocols.A. Inulin clearances following 5 days of obstruction and 5 days of recovery in obstructed () and contralateral (▪) kidneys. BMP-7 and enalapril were begun at the time of UUO (prevention protocol). B. Inulin clearances following 3 days of obstruction and 7 days of recovery in obstructed (▪), control (), and sham-operated ( ) kidneys. BMP-7 and enalapril were begun at the time of UUO. C. Inulin clearances following 3 days of obstruction and 7 days of recovery in obstructed (▪), contralateral (), and sham-operated kidneys. BMP-7 and enalapril were begun at the time of release of the UUO (treatment protocol). In each protocol, BMP-7, 100 μg/kg bw, was significantly more effective than enalapril in restoring GFR toward normal. Kidney International 2002 61, 1911-1922DOI: (10.1046/j.1523-1755.2002.00331.x) Copyright © 2002 International Society of Nephrology Terms and Conditions

Figure 3 BMP-7 prevents renal fibrogenesis following UUO. Coronal sections of kidneys stained with the Masson trichrome stain for collagen. With this stain, collagen fibrils stain blue, whereas the cells stain red. A, B are sections from the cortices of both kidneys of sham-operated animals. Collagen is detected in the renal capsule around larger vessels and Bowman's capsule. Little collagen is detectable in the renal interstitium. C, D are sections from two different areas of the obstructed kidney of a vehicle-treated animal. There is widespread and diffuse blue stain of the interstitial collagen, and a major interstitial cellular infiltrate. E, F are two sections of the cortex of an obstructed kidney from an animal treated with 100 μg/day bw of BMP-7. The amount of interstitial collagen is only slightly more than that in the sham-operated kidneys. G, H are two sections from the cortex of a kidney from an animal treated with 300 μg/day bw of BMP-7. The amount of interstitial collagen is indistinguishable from the interstitial collagen deposition in the sham-operated animals. [Reprinted with permission of the American Physiology Society from Am J Physiol (Renal Physiol) 280:F130-F143, 2000.] Kidney International 2002 61, 1911-1922DOI: (10.1046/j.1523-1755.2002.00331.x) Copyright © 2002 International Society of Nephrology Terms and Conditions

Figure 4 BMP-7 blocks development of tubular atrophy following UUO. Coronal sections of kidneys stained with the periodic-acid Schiff stain to highlight basement membranes. A. Sham-operated kidney. Basement membranes (BMs) are thin, BMs of different tubule segments often abut each other, and no interstitial infiltrate is present. B. Vehicle-treated kidney. UUO for 5 days with release and analysis at day 10. Heavy interstitial infiltrate and small atrophic tubules with thickened basement membranes. Some tubules have white blood cells in the lumens. C. 300 μg/kg bw of BMP-7 every other day. The pattern of basement membrane expression has basically been preserved as normal. D. Enalapril, 25 mg/kg daily. The cellular infiltrate is less than that with vehicle treatment (B), but the tubular atrophy is essentially unchanged compared with the vehicle-treated group. Kidney International 2002 61, 1911-1922DOI: (10.1046/j.1523-1755.2002.00331.x) Copyright © 2002 International Society of Nephrology Terms and Conditions

Kidney International 2002 61, 1911-1922DOI: (10. 1046/j. 1523-1755 Kidney International 2002 61, 1911-1922DOI: (10.1046/j.1523-1755.2002.00331.x) Copyright © 2002 International Society of Nephrology Terms and Conditions